Project Summary/Abstract Psychostimulants, including methamphetamine (METH), are a widely abused class of drugs that exert robust reinforcing and arousal-enhancing effects, contributing to their use and abuse. METH addiction is a disorder in which both humans and animals ultimately transition from nondependent episodic drug use to compulsive drug taking. Compulsivity in rodent drug addiction models is characterized by excessive patterns of drug seeking/taking behavior, including escalation of drug intake, increased motivation to obtain the drug (i.e. elevated progressive ratio breakpoints, drug taking in the face of punishment), reward system deficits during abstinence from the drug, and increased likelihood of relapse (Ahmed et al., 2002; Wee et al., 2007; Mantsch et al., 2008). Compulsive METH taking, in part, occurs through neuroadaptations of brain stress systems, particularly within the extended amygdala, that mediate negative emotional states implicated in motivational processes required for maintaining the dependent drug state (for review, see Koob, 2008). The lateral hypothalamus has been implicated in reward, stress and arousal systems, largely via hypocretin/orexin (HCRT) projection neurons located solely within the dorsal hypothalamus (for review, Boutrel et al., 2010; Marchant et al., 2012). HCRT neurotransmission has consistently been shown to play a role in nicotine, ethanol, and heroin self-administration behavior in rats. However, the direct contribution of the HCRT brain stress system to the emergence of compulsive behaviors associated with METH self-administration remains to be elucidated. In addition to a role in addiction, HCRT is posited to play a significant role in the regulation of arousal (for review, de Lecea et al., 2012). Interestingly, a number of clinical studies indicate associations between sleep dysfunction and drug abuse and/or relapse (Brower et al., 2001; Pace-Schott et al., 2005; Teplin et al., 2006). Despite these observations, few preclinical studies have been conducted investigating the direct or causative role for circadian system disruption in substance abuse, representing a significant lacuna in our understanding. Furthermore, there are currently no published studies focused on the contribution of HCRT neurotransmission to compulsive-like METH taking/seeking. Thus, the goal of the current research proposal is to characterize the role of HCRT in the negative reinforcement that contributes to state-dependent and arousal- related motivational aspects of compulsive METH taking. To achieve this goal, we will use a combination of opto-and chemo-genetics manipulations, together with radiotelemetry sleep/wake data, to determine the degree to which HCRT participates in compulsive METH taking. We will use an extended access model of addiction and genetic manipulations of neurocircuitry to determine the degree to which HCRT neurotransmission contributes to state-dependent motivational aspects of compulsive METH taking in rats. In addition, we will characterize arousal state dysfunction of compulsive METH taking during drug dependence, abstinence, and relapse.